ABSTRACT Recent clinical and experimental data suggest a potential interaction between epilepsy and Alzheimer's disease (AD), with seizures occurring in approximately 20% or more of AD patients, often prior to the onset of cognitive impairment. Conversely, chronic epilepsy syndromes such as temporal lobe epilepsy (TLE) can exhibit AD neuropathology, supporting the hypothesis that chronic excitability may promote neurodegenerative changes. Our preliminary data in AD human brain tissue show alterations in neurotransmitter (NT), ion transporter and mTOR pathway that we and others have previously observed in chronic epilepsy and TLE. Furthermore, our pilot data in 5XFAD mouse model show similar alterations including mTOR upregulation earlier in life prior to the development of AD neuropathology. Across many epilepsy models, the mTOR pathway has been shown to be critical for epileptogenesis. We hypothesize that these epilepsy-associated factors regulating neuronal hyperexcitability will be greater in AD patients compared to controls, and possibly even higher in AD patients with seizures. In addition, we will use the 5XFAD mouse model to determine the time course of alterations in expression of these epilepsy-associated factors, as well as the mTOR pathway, in relationship with spontaneous seizure development. We will also determine whether seizure induction during a ?pre-symptomatic? stage will cause accelerated AD neuropathology in these mice. Finally, we will use the mTOR inhibitor rapamycin to perform a preclinical trial aimed at decreasing AD neuropathology associated with hyperexcitability and seizures in the 5XFAD mice. In Aim 1, we will use both human AD, TLE, and control cortical and hippocampal specimens to determine whether the expression of common biomarkers of epilepsy correlate with the severity of AD pathology and presence or absence of epilepsy. In Aim 2, these biomarkers of potential clinical interest will be then assessed in longitudinal studies using the validated 5XFAD mouse model, by monitoring the evolution of AD pathology, cognitive dysfunction, and spontaneous seizure activity at baseline (Aim 2a). Subsequently, in Aim 2b we will determine whether attenuating epileptogenesis with the mTOR inhibitor rapamycin will improve AD neuropathology and cognition in the AD mice. In Aim 2c we will assess the direct effects of induced seizures on the previous outcomes, and determine whether rapamycin can prevent or reverse these changes. All studies will be statistically powered, will use formal randomization procedures, and primary data analysis will be conducted in a blinded manner. We anticipate that our proposed work will provide strong evidence for a causal link between hyperexcitability, mTOR activation and neurodegeneration in AD, specifically that seizures may represent a treatable component of AD. Further, we aim to build a research platform that will allow us to explore preclinical treatments trials in the future.